This invention relates to structures attachable to catheters to deliver radiation to a treatment site in the body. In one application, the catheter is used to prevent or slow restenosis of an artery traumatized such as by percutaneous transluminal angioplasty (PTA).
PTA treatment of the coronary arteries, percutaneous transluminal coronary angioplasty (PTCA), also known as balloon angioplasty, is the predominant treatment for coronary vessel stenosis. Approximately 300,000 procedures were performed in the United States in 1990 and nearly one million procedures worldwide in 1997. The U.S. market constitutes roughly half of the total market for this procedure. The increasing popularity of the PTCA procedure is attributable to its relatively high success rate, and its minimal invasiveness compared with coronary by-pass surgery. Patients treated by PTCA, however, suffer from a high incidence of restenosis, with about 40% or more of all patients requiring repeat PTCA procedures or by-pass surgery, with attendant high cost and added patient risk.
Various attempts to prevent restenosis by use of drugs, mechanical devices, and other experimental procedures have had limited long term success. Stents, for example, dramatically reduce acute reclosure, and slow the clinical effects of smooth muscle cell proliferation by enlarging the minimum luminal diameter, but otherwise do nothing to prevent the proliferative response to the angioplasty induced injury.
Restenosis is now believed to occur at least in part as a result of injury to the arterial wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by hyperplastic growth of vascular cells in the region traumatized by the angioplasty which is termed neointimal hyperplasia. Neointimal hyperplasia narrows the lumen that was opened by the angioplasty, regardless of the presence of a stent, thereby necessitating a repeat PTCA or other procedure to alleviate the restenosis.
Preliminary studies indicate that intravascular radiotherapy (IVRT) has promise in the prevention or long-term control of restenosis following angioplasty. IVRT may also be used to prevent or delay stenosis following cardiovascular graft procedures or other trauma to the vessel wall. Proper control of the radiation dosage, however, appears to be important to inhibit or arrest hyperplasia without causing excessive damage to healthy tissue. Overdosing of a section of blood vessel can cause arterial necrosis, inflammation, hemorrhaging, and other risks discussed below. Underdosing will result in inadequate inhibition of smooth muscle cell hyperplasia, or even exacerbation of hyperplasia and resulting restenosis.
The prior art contains many examples of catheter based radiation delivery systems. The simplest systems disclose seed train type sources inside closed end tubes. An example of this type of system can be found in U.S. Pat. No. 5,199,939 to Dake. In order to separate the radiation source from the catheter and allow re-use of the source, a delivery system is disclosed by U.S. Pat. No. 5,683,345 to Waksman et al. where radioactive source seeds are hydraulically driven into the lumen of a closed end catheter where they remain for the duration of the treatment, after which they are pumped back into the container. Later disclosures integrated the source wire into catheters more like the type common in interventional cardiology. In this type of device, a closed end lumen, through which is deployed a radioactive source wire, is added to a conventional catheter construction. A balloon is incorporated to help center the source wire in the lumen. It is supposed that the radioactive source wire would be delivered through the catheter with a commercial type afterloader system produced by a manufacturer such as Nucletron, BV. These types of systems are disclosed in Liprie U.S. Pat. No. 5,618,266, Weinberger U.S. Pat. No. 5,503,613, and Bradshaw U.S. Pat. No. 5,662,580.
In the systems disclosed by Dake and Waksman, the source resides in or very near the center of the catheter during treatment. However, it does not necessarily reside in the center of the artery. The systems disclosed by Weinberger and Bradshaw further include a centering mechanism, such as an inflatable balloon, to overcome this shortcoming. In either case, the source activity and energy must be high enough to overcome absorption loss encountered as the radiation traverses the lumen of the blood vessel to get to the target tissue site in the vessel wall.
Higher activity and energy sources, however, can have undesirable consequences. First, the likelihood of radiation inadvertently affecting untargeted tissue is higher because the absorption factor per unit tissue length is lower. Second, the higher activity and energy sources are more hazardous to the medical staff and thus require additional shielding during storage and additional precaution during use. In addition, the source of any activity or energy may or may not be exactly in the center of the lumen, so the dose calculations are subject to error factors due to non-uniformity in the radial distance from the source surface to the target tissue. The impact of these factors is a common topic of discussion at recent medical conferences addressing Intravascular Radiation Therapy, such as the Trans Catheter Therapeutics conference, the Scripps Symposium on Radiotherapy, the Advances in Cardiovascular Radiation Therapy meeting, the American College of Cardiology meeting, and the American Heart Association Meeting.
The impact on treatment strategy is discussed in detail in a paper discussing a removable seed system similar to the ones disclosed above (Tierstein et al., Catheter based Radiotherapy to Inhibit Restenosis after Coronary Stenting, NEJM 1997; 336(24):1697-1703). Tierstein reports that Scripps Clinic physicians inspect each vessel using ultrasonography to assess the maximum and minimum distances from the source center to the target tissue. To prevent a dose hazard, they will not treat vessels where more than about a 4xc3x97differential dose factor (8-30 Gy) exists between the near vessel target and the far vessel target. Differential dose factors such as these are inevitable for a catheter in a curvilinear vessel such as an artery, and will invariably limit the use of radiation from conventional wire and seed train sources and add complexity to the procedure. Moreover, the paper describes the need to keep the source in a lead transport device called a xe2x80x9cpigxe2x80x9d, as well as the fact that the medical staff leaves the catheterization procedure room during the treatment. Thus added complexity, time and risk is added to the procedure caused by variability of the position of the source within the delivery system and by the activity and energy of the source itself.
A variety of additional structures have been disclosed, as alternatives to the wire and seed train systems. For example, U.S. Pat. No. 5,302,168 to Hess teaches the use of a radioactive source contained in a flexible carrier with remotely manipulated windows; Fearnot discloses a wire basket construction in U.S. Pat. No. 5,484,384 that can be introduced in a low profile state and then deployed once in place; Hess also purports to disclose a balloon with radioactive sources somehow attached on the surface in U.S. Pat. No. 5,302,168; Hehrlein discloses a balloon catheter which carries an active isotope on the balloon in WO 96/22121; and Bradshaw discloses a balloon catheter adapted for use with a liquid isotope in U.S. Pat. No. 5,662,580.
In a non-catheter based approach, U.S. Pat. No. 5,059,166 to Fischell discloses an IVRT method that relies on a radioactive stent that is permanently implanted in the blood vessel after completion of the lumen opening procedure. Close control of the radiation dose delivered to the patient by means of a permanently implanted stent is difficult to maintain because the dose is entirely determined by the activity of the stent at the particular time it is implanted. In addition, current stents are generally not removable without invasive procedures. The dose delivered to the blood vessel is also non-uniform because the tissue that is in contact with the individual struts of the stent receive a higher dosage than the tissue between the individual struts.
Another approach is to use a nuclide suspended in solution to inflate a balloon (Thornton ""114). This technique provides uniform nuclide distribution within the balloon to form the source, resulting in uniform dose patterns. Also, this configuration moves the position of the nuclide closer to the target tissue. A relatively conventional appearing catheter may be used for this type of approach, and many nuclides are available in liquid form. Hence, several investigators have begun clinical studies on so-called radioactive liquid filled balloons.
While in some ways appearing to provide a solution to the problem of centering, the liquid filled balloon systems have other drawbacks. For example, as is known to those familiar with the design, manufacture, or use of balloon angioplasty catheters, balloons potentially break. If a balloon is used to contain an active nuclide, a break poses an obvious health threat to the patient, physician and any nearby laboratory personnel. A break or leak may also shut down the procedure room. In addition, the activity to achieve a desired delivered dose is still relatively high. The distribution of isotope throughout the radius of the balloon acts like a source spaced apart from the vessel wall with a resulting decay in activity before reaching the target tissue.
In all of the foregoing designs, full containment of the isotope remains a significant challenge. The American National Standards Institute (ANSI) publishes a standard for sealed sources (ANSI N44.1-1973 Integrity and Test Specifications for Selected Brachytherapy Sources), and the US Nuclear Regulatory Commission (NRC) defines a sealed source as containing less than 5 nanoCuries (5xc3x9710xe2x88x929 Curies) of removable activity. Hehrlein reported (Scripps Conference, January 1998) a balloon coated with P-32 that lost 0.5% of its contained activity in an animal study. Even with only 1 mCi of contained activity, the balloon proposed by Hehrlein would have lost 5000 nCi, well beyond NRC standards for a sealed source, and well outside of the ANSI definition of a sealed source.
Despite the foregoing, among many other advances in IVRT, there remains a need for an IVRT method and apparatus that delivers an easily controllable uniform dosage of radiation without the need for special devices or methods to center a radiation source in the lumen. Furthermore, a need remains for a radiation delivery device which is similar in use to conventional angioplasty balloon catheters, and which has a sealed source to prevent escape of radioactive species.
There is provided in accordance with one aspect of the present invention, a method of optimizing an in stent radiation delivery profile, comprising the steps of identifying a stent positioned against the wall of a vessel; positioning a radiation source within the stent; and exposing the vessel to radiation through the stent such that variations in the dose delivered to a depth of about 1 mm in the wall of the vessel along the length of the source do not exceed about 50%, and preferably do not exceed about 20%.
In accordance with another aspect of the invention, there is provided a radiation delivery catheter for in stent delivery of a substantially uniform dose of radiation, comprising an elongate, flexible, tubular body, having a proximal end and a distal end; and a radiation source near the distal end, wherein the source is capable of a substantially uniform delivery of radiation at a depth of about 1 mm in tissue behind the stent along a length of at least about 30% of the length of the source.
In accordance with another aspect of the present invention, there is provided a method of treating tissue, comprising delivering radiation at a dose of at least about 8 Gy, at a depth of 1 mm into the tissue, over a time of less than about 20 minutes, and preferably less than about 15 minutes. In different applications of the invention, the tissue is in the coronary arteries, carotid arteries, intra-cranial vasculature, peripheral vasculature, vascular anastomoses anywhere in the body and in one application on saphenous vein grafts, the esophagus, trachea, airways of the lung, stomach, intestines, rectum, uterus, fallopian tubes, or other hollow organs, lumens or surgically created pathways in the body.
In accordance with another aspect of the present invention, there is provided a radiation delivery catheter, for delivering a dose of radiation within a vessel, comprising an elongate flexible body, having a proximal end and a distal end; and a radiation source carried by the body near the distal end thereof; wherein the source is configured to deliver a dose in excess of about 8 Gy at a depth of 1 mm into the vessel wall over a time period of no more than about 15 minutes.
In accordance with another aspect of the present invention, there is provided a method of optimizing radiation dose uniformity in a vessel wall behind a stent, comprising the steps of positioning a radiation delivery catheter within a stent in a body vessel, delivering a first dose of beta radiation along a first axis past a first side of a stent strut and into the vessel wall; and delivering a second dose of beta radiation along a second axis past a second side of the strut and into the vessel wall; wherein the first axis and the second axis converge behind the strut to deliver a desired dose behind the strut.
In accordance with a further aspect of the present invention, there is provided a method of optimizing an intraluminal radiation delivery profile, comprising the steps of identifying a treatment site in the wall of a vessel; positioning a radiation source against the wall; and exposing the vessel to radiation such that variations in the dose delivered to a depth of about 1 mm in the wall of the vessel along the length of the source do not exceed about 50%, and preferably do not exceed about 20%.
In accordance with yet another aspect of the present invention, there is provided a radiation delivery catheter for delivering a substantially uniform dose of radiation, comprising an elongate, flexible, tubular body, having a proximal end and a distal end; and a radiation source near the distal end; wherein the source is capable of a substantially uniform delivery of radiation at a depth of about 1 mm into the wall of the vessel along a length of at least about 30% of the length of the source.
In accordance with yet another aspect of the present invention, there is provided a method of optimizing a radiation delivery profile in a peripheral vessel, with or without a stent at the treatment site, comprising the steps of identifying a treatment site in a vessel, positioning a radiation source at the site; and exposing the vessel to radiation such that variations in the dose delivered to a depth of about 2 mm in the wall of the vessel along the length of the source do not exceed about 20%.
In accordance with another aspect of the present invention, there are provided methods for making radiation delivery catheters having non-uniform, non-homogeneous, or discontinuous sources. Such sources include, but are not limited to, those having higher or lower activity on different areas of the source, sources in which some areas of the source contain one or more additional layers, sources having slits, notches or grooves, sources comprising a plurality of source strips which are spaced apart by a minor amount, sources having greater activity near the ends of their length (extended effective radiaiton length), and sources having reduced activity at their ends. The methods for making such sources include use of techniques such as masking, etching, variable reaction times, inhomogeneous deposition of source layers, ion implantation, plastics extrusion and molding, electrodeposition, adsorption, and metal sheet stamping.
In accordance with another aspect of the present invention there is provided a method for treating lesions having a length greater than that of the source used for treatment. In this method, a radiation delivery catheter is provided in which the source has bands of reduced activity at the proximal and distal ends of the source. After insertion, the source on the catheter is placed at two or more generally adjacent positions in the area of the lesion, in series, allowing for some overlap of the regions with reduced activity.
Further features and advantages of the present invention will become apparent to those of skill in the art in view of the detailed description of preferred embodiments which follow, when considered together with the attached drawings and claims.